The present invention relates to a process for preparing terpyridines of the formula I 
in which
R are hydrogens or identical C1-C12-alkyl or C1-C12-alkoxy radicals and
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals
by successive reaction steps comprising
A) condensation of a C1-C4-alkyl pyridine-2-carboxylate derivative with acetone in an aprotic solvent in the presence of a base,
B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative obtained in reaction step A with ammonia or ammonium salts (NH4)qY with removal of the water of reaction formed, where the variable Y in (NH4)qY is the anion of the parent q-basic acid HqY of the ammonium salt, and
C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative obtained in reaction step B,
wherein the reaction step A is preceded by a reaction step Axe2x80x2 in which the C1-C4-alkyl pyridine-2-carboxylate derivative is obtained by
Axe2x80x2) acid hydrolysis of a 2-cyanopyridine derivative by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C1-C4-alkanol, with an equimolar amount of water being added to the 2-cyanopyridine derivative of the formula a prior to addition of the anhydrous inorganic acid or its anhydride,
the base used in reaction step A is an alkali metal C1-C4-alkoxide or alkaline earth metal C1-C4-alkoxide,
the removal of the water of reaction in reaction step B is carried out using a C1-C4-alkanol as entrainer
and
the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c in reaction step C is carried out using phosphorus oxide chloride (POCl3) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.
The present invention further relates to a process for preparing C1-C4-alkyl pyridine-2-carboxylate derivatives from 2-cyanopyridine derivatives, to a process for preparing 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives by condensation of a C1-C4-alkyl pyridine-2-carboxylate derivative with acetone, to a process for preparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives by reaction of a 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative with ammonia or ammonium salts and to a process for preparing terpyridines of the formula I by chlorination of a 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative.
The interest in oligopyridines is tremendous, particularly because they are excellent complexing agents for metals. As a result, a wide variety of synthetic routes have been employed for these compounds. A review is given, for example, by R. -A. Fallahpour in Synthesis 2000, No. 12, 1665-1667.
The synthesis of 4xe2x80x2-chloro-2,2xe2x80x2:6xe2x80x2,6xe2x80x3-terpyridine from ethyl pyridine-2-carboxylate via the intermediates 1,5-bis(2-pyridyl)pentane-1,3,5-trione and 2,6-bis(2-pyridyl)-4(1H)pyridinone is described by E. C. Constable and M. D. Ward in J. Chem. Soc. Dalton Trans. 1990, 1404-1409 (1). The condensation of the pyridinecarboxylic ester with acetone (corresponding to reaction step A of the process of the present invention) is carried out in the presence of sodium hydride as base. The resulting pentane-1,3,5-trione is then reacted with ammonium acetate under reflux to form the corresponding 4(1H)pyridinone (corresponding to reaction step B of the process of the present invention), which then reacts with an excess of phosphorus pentachloride in phosphorus oxide chloride as solvent to give the desired terpyridine (corresponding to reaction step C of the process of the present invention). The respective yields of the reactions corresponding to the reaction steps A, B and C are said by the authors to be 80%, 80% and 62%, respectively, which corresponds to an overall yield of terpyridine based on the pyridinecarboxylic ester used of about 40%.
According to R. L. Frank and E. F. Riener, J. Am. Chem. Soc., Vol. 72, 4182-4183 (2), ethyl picolinate (ethyl pyridine-2-carboxylate) is prepared by reacting 2-cyanopyridine with ethanol saturated with HCl gas. The imino ester formed as intermediate is then hydrolyzed to the ethyl ester by pouring into water. The yield of this reaction is said to be 40%.
Serious disadvantages of the procedure described in (1) are the use of extremely air- and moisture-sensitive sodium hydride and of large amounts of corrosive and toxic phosphorus pentachloride or phosphorus oxide chloride and the generally high starting material costs for pyridinecarboxylic esters. For these reasons, this route to terpyridines can be employed only with great difficulty, if at all, on a (large) industrial scale.
An attractive starting material for the synthesis of terpyridines is 2-cyanopyridine, because of the price advantage over pyridinecarboxylic esters. 2-Cyanopyridine can be converted as described in (2) into ethyl pyridinecarboxylates, but the synthesis described in (2) has the disadvantage that, based on the amount of 2-cyanopyridine used, only a small yield of the desired ester is obtained, which cancels out the price advantage. If the yield reported in (2) is multiplied by the yield of about 40% indicated above, the overall yield of terpyridine starting from 2-cyanopyridine is only about 16%. This is prohibitively low for (large-scale) industrial processes.
It is an object of the present invention to provide an inexpensive process for preparing terpyridines from 2-cyanopyridine which can be carried out on a (large) industrial scale and is acceptable from the points of view of occupational hygiene and the environment.
We have found that this object is achieved by a process for preparing terpyridines of the formula I 
in which
R are hydrogens or identical C1-C12-alkyl or C1-C12-alkoxy radicals and
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,
by successive reaction steps comprising
A) condensation of a C1-C4-alkyl pyridine-2-carboxylate derivative of the formula a 
xe2x80x83with acetone in an aprotic solvent in the presence of a base,
B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative of the formula b 
xe2x80x83obtained in reaction step A with ammonia or ammonium salts (NH4)qY with removal of the water of reaction formed, where the variable Y in (NH4)qY is the acid anion of the parent q-basic acid HqY of the ammonium salt, and
C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c obtained in reaction step B 
xe2x80x83where Z is NH in the case of a reaction with ammonia in reaction step B and is NH2⊕[Y1/q]xe2x8ax96 in the case of a reaction with ammonium salts (NH4)qY in reaction step B,
wherein
the reaction step A is preceded by a reaction step Axe2x80x2 in which the C1-C4-alkyl pyridine-2-carboxylate derivative of the formula a is obtained by
Axe2x80x2) acid hydrolysis of a 2-cyanopyridine derivative of the formula axe2x80x2 
xe2x80x83by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C1-C4-alkanol, with an equimolar amount of water being added to the 2-cyanopyridine derivative of the formula axe2x80x2 prior to addition of the anhydrous inorganic acid or its anhydride,
the base used in reaction step A is an alkali metal C1-C4-alkoxide or alkaline earth metal C1-C4-alkoxide,
the removal of the water of reaction in reaction step B is carried out using a C1-C4-alkanol as entrainer
and
the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c in reaction step C is carried out using phosphorus oxide chloride (POCl3) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.
In formula a, C1-C4-alkyl radicals are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl, so that the corresponding C1-C4-alkanols with which the 2-cyanopyridines of the formula axe2x80x2 are reacted to form the compounds of the formula a are methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, sec-butanol and tert-butanol.
The latter listing also encompasses the C1-C4-alkanols which are used in reaction step B as entrainers for removing the water of reaction. The alkanols used in steps Axe2x80x2 and B do not necessarily have to be identical.
C1-C12-Alkyl radicals R in the formulae I, a, b, c and axe2x80x2 can be, in addition to the abovementioned C1-C4-alkyl radicals, pentyl, sec-pentyl, tert-pentyl, neopentyl, 2,3-dimethyl-2-butyl, hexyl, 2-methylpentyl, heptyl, 2-methylhexyl, 2-ethylhexyl, octyl, isooctyl, 2-ethylhexyl, nonyl, 2-methylnonyl, isononyl, 2-methyloctyl, decyl, isodecyl, 2-methylnonyl, undecyl, isoundecyl, dodecyl and isododecyl, (the names isooctyl, isononyl and isodecyl are trivial names and are derived from the carbonyl compounds obtained in the oxo process; cf. Ullmann""s Encyclopedia of Industrial Chemistry, 5th Edition, Vol. Al, pages 290-293, and Vol. Alo, pages 284 and 285).
C1-C12-Alkoxy radicals R in the formulae I, a, b, c and axe2x80x2 and the C1-C4-alkoxide radicals of the alkali metal or alkaline earth metal alkoxides to be used as bases in step A are derived from the abovementioned C1-C12-alkyl or C1-C4-alkyl radicals.
To convert the 2-cyanopyridine derivative of the formula axe2x80x2 into the corresponding C1-C4-alkyl pyridine-2-carboxylate of the formula a, the former is usually dissolved or suspended in an excess of the corresponding absolute C1-C4-alkanol, admixed with the equivalent amount of water, based on the number of moles of the compound of the formula axe2x80x2, and the anhydrous inorganic acid is added, if appropriate a little at a time. It is naturally also possible to use alkanols with their typical residual water contents, in which case the amount of water is then reduced correspondingly.
The molar ratio of 2-cyanopyridine derivative to inorganic acid is usually from 1:4 to 1:10, and that of 2-cyanopyridine derivative to C1-C4-alkanol is usually from 1:15 to 1:40.
The reaction conditions in reaction step Axe2x80x2 are usually chosen in a manner analogous to the conditions in the Pinner reaction leading to the imino esters, i.e. the inorganic acid is added at room temperature or slightly elevated temperature, which normally results in a further temperature increase due to the exothermic character of the reaction. The mixture is then usually allowed to react to completion under reflux.
The crude product obtained is generally worked up by distilling off the excess C1-C4-alkanol, taking up the residue in a suitable solvent and, to avoid possible hydrolysis of the ester formed, washing until neutral with the solution of a weak base, e.g. an aqueous sodium bicarbonate solution. After phase separation, the resulting solution of the product can, if a suitable aprotic solvent has been used, be processed further directly as described in step A or an appropriate solvent replacement has to be carried out beforehand.
Examples of anhydrous inorganic acids are anhydrous sulfuric acid, fuming sulfuric acid, anhydrous phosphoric acid, anhydrous pyrophosphoric acid and hydrogen chloride, with preference being given to using the latter.
Examples of anhydrides of these inorganic acids are sulfur trioxide and tetraphosphorus decaoxide.
As alkali metals or alkaline earth metals of the alkoxides in step A, particular mention may be made of sodium and potassium and also magnesium and calcium, especially sodium. Preference is accordingly given to using sodium C1-C4-alkoxides, in particular sodium methoxide.
Aprotic solvents which can be used in step A are generally well known to those skilled in the art. Examples are cyclic ethers such as tetrahydrofuran or dioxane, and also linear and branched glycol ethers which are obtainable from ethylene oxide and propylene oxide. Examples of such ethers are dimethoxyethane (DME) and further dimethyl ethers which are commercially available under the name Glyme(copyright).
The reaction conditions in step A correspond to the usual conditions of the Claisen condensation, i.e. the reaction is normally carried out under reflux at the boiling point of the solvent used.
The molar ratio of ester derivative of the formula a to acetone is usually 2:1, corresponding to the stoichiometry of the reaction. In specific cases, slightly above or slightly below this ratio may be desirable.
The crude product obtained in step A is generally sufficiently pure and can therefore normally be used as starting material for reaction step B without elaborate purification. Thus, after adjusting the pH to a neutral or slightly acid value by means of a weak acid, e.g. acetic acid or the ammonium salt (NH4)qY to be used in step B, the entrainer for step B can be added directly to the solution/suspension obtained in step A.
However, if higher purities are required, it is possible to separate off the aprotic solvent used in step A, dissolve or suspend the residue in water, add a weak acid, e.g. acetic acid, until the pH is neutral or slightly acid, filter off the usually solid reaction product with suction and wash it with a little water. If necessary, this can be followed by a drying step.
As solvent or suspension medium in reaction step B, use is made of the C1-C4-alkanol serving as entrainer. The molar ratio of trione derivative of the formula b to alkanol is usually from 1:75 to 1:125.
The removal of the water of reaction in reaction step B is carried out using customary methods of water separation. If the alkanol serving as entrainer has only limited miscibility with water, for instance in the case of the various C4-alkanols, the water can be removed, for example, by discharging it after phase separation and the alkanol can be returned to the reaction mixture. If the alkanol and water have unlimited miscibility, the water can be separated off by distillation together with the alkanol and the latter can be worked up in a separate distillation step.
The reaction temperature in step B corresponds essentially to the customary temperatures in the refluxing C1-C4-alkanol/water mixture, with lower temperatures or temperature profiles also being able to be set at the beginning of the reaction.
Preferred entrainers in reaction step B are ethanol, n-propanol, i-propanol and n-butanol, with particular preference being given to ethanol.
Possible ammonium salts (NH4)qY with which the trione obtained in step A is reacted in reaction step B are, for example, the ammonium salts of formic, acetic, carbonic, hydrochloric, sulfuric or phosphoric acid, i.e. NH4HCO2 (q=1, Y=HCO2xe2x8ax96), NH4CH3CO2 (q=1, Y=CH3CO2xe2x8ax96), NH4HCO3 (q=1, Y=HCO3xe2x8ax96(NH4)2CO3 (q=2, Y=CO32xe2x8ax96), NH4Cl (q=1, Y=Clxe2x8ax96), NH4HSO4 (q=1, Y=HSO4xe2x8ax96), (NH4)2SO4 (q=2, Y=SO42xe2x8ax96), NH4H2PO4 (Y=H2PO4xe2x8ax96) und (NH4)2HPO4 (q=2, Y=HPO42xe2x8ax96). Preference is given to using ammonia in step B.
The ammonium salts are usually used as solids if appropriate with their typical contents of water of crystallization, and ammonia is usually used as gas. However, aqueous solutions can also be used if desired, in which case not only the water arising in the formation of the 4(1H)pyridinone derivative but also the water of the solution are removed by means of the entrainer in step B.
The ammonium salts are generally added in a molar ratio of ammonium ion:trione of from 3:1 to 12:1, preferably in a molar ratio of from 5:1 to 10:1.
The gaseous ammonia is introduced into the reaction mixture as a finely divided stream, e.g. through a frit, until a molar ratio of the total amount of ammonia:trione of from 6:1 to 14:1, preferably from 8:1 to 12:1, has been reached. The introduction of the ammonia gas can be carried out initially at temperatures or temperature profiles below reflux conditions or right from the start under the conditions of removal of the water of reaction, i.e. under reflux.
The crude product obtained in step B is usually worked up by distilling off the remaining C1-C4-alkanol, suspending the residue in water, filtering it off with suction, washing it with water and a little (!), optionally (ice) cooled, ethanol and finally drying it.
The pyridinone obtained in step B is reacted in step C with phosphorus oxide chloride (POCl3) or with a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene. The reaction is generally carried out under reflux with boiling of the phosphorus oxide chloride or the mixture of phosphorus oxide chloride and organic solvent.
The molar ratio of pyridinone of the formula c to phosphorus oxide chloride is usually from 1:5 to 1:25, in particular from 1:8 to 1:20. If a mixture of phosphorus oxide chloride and organic solvent is used, the molar excess of phosphorus oxide chloride over the pyridinone can be reduced.
The molar ratio of phosphorus oxide chloride to the organic solvent is usually from 0.8:1 to 2:1, in particular from 1:1 to 1.5:1.
The crude product obtained in step C is normally worked up by removing (e.g. distilling off) the excess phosphorus oxide chloride or the mixture of phosphorus oxide chloride and organic solvent, dissolving the residue (ammonium salt!) in water, bringing the pH to 7 by adding concentrated alkali (e.g. sodium hydroxide solution, sodium carbonate solution) or a basic compound (e.g. sodium hydroxide, sodium carbonate), filtering off the resulting precipitate with suction, washing with water and finally drying the solid.
The present invention further provides a process for preparing C1-C4-alkyl pyridine-2-carboxylate derivatives of the formula a 
in which
R is hydrogen or a C1-C12-alkyl or C1-C12-alkoxy radical and
n is 0, 1, 2, 3 or 4,
by acid hydrolysis of a 2-cyanopyridine derivative of the formula axe2x80x2 
by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C1-C4-alkanol, wherein an equimolar amount of water is added to the 2-cyanopyridine derivative of the formula axe2x80x2 prior to addition of the anhydrous inorganic acid or its anhydride.
Reaction conditions for this process have already been described under step Axe2x80x2 of the process of the present invention for preparing terpyridines of the formula I from 2-cyanopyridine derivatives of the formula axe2x80x2 and apply analogously here.
The present invention also provides a process for preparing 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives of the formula b 
in which
R are hydrogens or identical C1-C12-alkyl or C1-C12-alkoxy radicals and
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,
by condensation of the C1-C4-alkyl pyridine-2-carboxylate derivative of the formula a 
with acetone in an aprotic solvent in the presence of an alkali metal C1-C4-alkoxide or alkaline earth metal C1-C4-alkoxide as base.
Bases used are, in particular, alkali metal C1-C4-alkoxides, preferably sodium C1-C4-alkoxides and particularly preferably sodium methoxide.
Further reaction conditions for this process have been described under step A of the process of the present invention for preparing terpyridines of the formula I from 2-cyanopyridine derivatives of the formula axe2x80x2 and apply analogously here.
Furthermore, the present invention provides a process for preparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives of the formula c 
in which
R are hydrogens or identical C1-C12-alkyl or C1-C12-alkoxy radicals,
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,
Z is NH or NH2xe2x8ax96[Y1/q]xe2x8ax96 and
Y is the anion of a q-basic acid HqY,
by reacting the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative of the formula b 
with ammonia or ammonium salts (NH4)qY with removal of the water of reaction formed, wherein the removal of the water of reaction is carried out using a C1-C4-alkanol as entrainer.
As entrainer for removing the water of reaction, use is made, in particular, of ethanol, n-propanol, i-propanol or n-butanol, with preference being given to ethanol.
Further reaction conditions for this process have already been described under step B of the process of the present invention for preparing terpyridines of the formula I from 2-cyanopyridine derivatives of the formula axe2x80x2 and apply analogously here.
Also provided is a process for preparing terpyridines of the formula I 
in which
R are hydrogens or identical C1-C12-alkyl or C1-C12-alkoxy radicals,
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals
Zxe2x80x2 is nitrogen or NH⊕[Y1/q]xe2x8ax96 and
Y is the acid anion of a q-basic acid HqY,
by chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula b 
where Z is NH or NH2⊕[Y1/q]xe2x8ax96,
wherein the chlorination is carried out using phosphorus oxide chloride (POCl3) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.
Chlorinating agents which can be used are, in particular, phosphorus oxide chloride (POCl3) or a mixture comprising phosphorus oxide chloride and toluene.
Further reaction conditions-for this process have already been described under step C of the process of the present invention for preparing terpyridines of the formula I from 2-cyanopyridine derivatives of the formula axe2x80x2 and apply analogously here.